Christian-Albrechts-University Kiel, Institute of Biochemistry, 24118 Kiel, Germany.
Institute of Molecular Cell Biology, CMB, Jena University Hospital, Jena, Germany.
Trends Mol Med. 2020 Sep;26(9):833-847. doi: 10.1016/j.molmed.2020.06.002. Epub 2020 Jun 24.
Activating mutations in genes encoding receptor tyrosine kinases (RTKs) mediate proliferation, cell migration, and cell survival, and are therefore important drivers of oncogenesis. Numerous targeted cancer therapies are directed against activated RTKs, including small compound inhibitors, and immunotherapies. It has recently been discovered that not only certain RTK fusion proteins, but also many full-length RTKs harbouring activating mutations, notably RTKs of the class III family, are to a large extent mislocalised in intracellular membranes. Active kinases in these locations cause aberrant activation of signalling pathways. Moreover, low levels of activated RTKs at the cell surface present an obstacle for immunotherapy. We outline here why understanding of the mechanisms underlying mislocalisation will help in improving existing and developing novel therapeutic strategies.
受体酪氨酸激酶（RTKs）编码基因中的激活突变可介导增殖、细胞迁移和细胞存活，因此是致癌的重要驱动因素。许多针对激活 RTK 的靶向癌症疗法包括小分子抑制剂和免疫疗法。最近发现，不仅某些 RTK 融合蛋白，而且许多含有激活突变的全长 RTK，特别是 III 类 RTK，在很大程度上被错误地定位在内质网膜上。这些位置的活性激酶导致信号通路的异常激活。此外，细胞表面低水平的激活 RTK 会给免疫治疗带来障碍。我们在这里概述了为什么对定位错误机制的理解将有助于改进现有和开发新的治疗策略。
